Many therapeutic agents typified by chemotherapeutics are effective at treating a particular condition, but may at the same time have toxic side effects for the patients that significantly impact the quality of life for the patient. These toxic side effects may arise through the biological action of the agents. For example, a majority of chemotherapy agents kill cancer cells by acting on cells that are actively dividing and replicating. These agents unfortunately do not discriminate between cancer cells and actively dividing normal cells such as blood cells forming bone marrow, cells in the digestive tract, hair follicles, and reproductive cells. Because the chemotherapeutic agents are toxic, the effectiveness of the drug is limited because dosage levels and treatment frequency cannot exceed tolerance levels for non-cancerous cells. Moreover, the chemotherapy regimen often dramatically diminishes the quality of a patient's life through its physical and emotional side effects.
In attempts to overcome the problems of toxicity, chemotherapeutic agents have been targeted to tumor cells by covalently binding the agent to a carrier macromolecule that binds a specific receptor on the surface of a target cell. The carrier molecule is commonly a protein or glycoprotein but may also be a carbohydrate. Limitations of this approach include the ability of the conjugate to effectively and selectively bind the drug target.
An alternative approach to treating patients is to search for therapeutic agents that act on targets that are only associated with diseased tissue. For example, certain cancer drugs are being developed that inhibit angiogenesis, an activity that is essential for growth of a tumor but not otherwise essential in an adult subject except for wound healing or during the menstrual cycle. Another approach is to inhibit tumor metastasis. Potential anti-metastatic agents include a class of modified citrus pectins which are polysaccharides that prevent metastasis of primary tumors by acting as antagonists for growth factors that interact with cell receptors to prevent metastasized cells from lodging at a secondary site (Platt et al. J. Natl Cancer Inst. 84, 438-442 (1992); U.S. Pat. No. 5,801,002, Raz, U.S. Pat. No. 5,895,784). Carbohydrate binding proteins have also been used to prevent metastasis of tumors. These compounds are galactose specific carbohydrate binding proteins that bind to galactose binding sites on metastatic cells and interfere with cell-cell interactions necessary during metastasis. (Platt: U.S. Pat. No. 5,681,923). Simple sugars such as methyl-∀-D lactoside and lacto-N-tetrose have been shown to inhibit metastasis of B16 melanoma cells, while D-galactose and arabinogalactose inhibited liver metastasis of L-1 sarcoma cells (Beuth et al. J. Cancer Res. Clin. Oncol. 113, 51, 1987).
Despite the increasing resources applied to develop new therapies for cancer, survival rates for most cancer patients have not materially improved over the last 15 years (American Cancer Society, 1995 “Cancer Facts & Figures”). In most cases, particularly when a tumor is not detected at an early stage, cancer chemotherapy merely partially prolongs a patient's life, often for only a few months. Given the rigors of repeated chemotherapeutic treatments, and taking into account the low response rates and the modest effects on survival time, significant toxicity and side effects which reduce the patient's quality of life have become a major issue. Increasing efficacy of a drug can be translated into decreasing of the dosage of the drug, and decreasing its toxicity. Further, decreasing of toxicity per se leads to improvement of the patient's quality of life.
However effective a therapeutic agent may be in modifying an abnormal biological condition, undesirable toxic side-effects impinge on the optimum use of the agents.